Project 4, in its modified form, is a randomized, placebo-controlled, double-blind, three-armed lung cancer chemoprevention trial in former smokers. Our specific aims are: (a) To determine the efficacy of 9-cis retinoic acid (9cRA) and 13- cis retinoic acid (l 3cRA) plus (alpha- tocopherol in reversing biomarkers of lung carcinogenesis, such as genetic and histologic alterations of preneoplasia and in activating biomarkers of retinoid response in the bronchial epithelium of former smokers; (b) To correlate the reversal of histologic and genetic abnormalities with retinoid nuclear receptor activation in bronchial biopsies from patients enrolled on the chemoprevention trial; (c) To explore the retinoid signaling pathways that mediate retinoid actions, such as inhibition of growth and squamous differentiation in normal human bronchial epithelial (HBE) cells, and the role of specific nuclear receptors and target genes activated by the receptors. The accrual goal for the chemoprevention trial is 225 patients. Accrual has recently increased appreciably due to enhanced efforts in patient recruitment, and at the time of grant submission we expect to have reached 50% of the accrual goal. Changes in eligibility Criteria and treatment schedule have been made in the clinical trial to enhance patient accrual and reduce treatment-associated toxicity, respectively. Progress has been made toward the completion of biomarker studies proposed in Aim 2 through close interactions between the two University of Texas Institutions participating in this SPORE. These investigations have revealed that genetic abnormalities such as loss of heterozygosity and genomic instability are prevalent on chromosomes 3p, 9p and 17p in the bronchial epithelium of former smokers. Other biomarkers studies investigating the expression of retinoic acid receptor (RAR)beta and telomerase activity in bronchial biopsies are ongoing. Through an active, inter-institution collaboration between Drs. Jonathan Kurie and David Mangelsdorf, progress has been made in translational studies proposed in Aim 3, revealing the importance of c-Jun N-terminal kinase in retinoid signaling. Future directions of this collaboration will identify, through cDNA subtraction and gene array technologies, novel genes targeted by retinoid receptors that mediate growth inhibition of normal HBE cells and retinoid resistance in non-small cell lung cancer cells.